The disclosure of each literature article and published patent document referred to herein is incorporated by reference in its entirety.
The National Cancer Institute has estimated that in the United States alone, 1 in 3 people will be struck with cancer during their lifetime. Moreover, approximately 50% to 60% of people contracting cancer will eventually succumb to the disease. The widespread occurrence of this disease underscores the need for improved anticancer regimens for the treatment of malignancy.
Due to the wide variety of cancers presently observed, numerous anticancer agents have been developed to destroy cancer within the body. These compounds are administered to cancer patients with the objective of destroying or otherwise inhibiting the growth of malignant cells while leaving normal, healthy cells undisturbed. Anticancer agents have been classified based upon their mechanism of action.
One type of chemotherapeutic is referred to as a metal coordination complex. It is believed this type of chemotherapeutic forms predominantly inter-strand DNA cross links in the nuclei of cells, thereby preventing cellular replication. As a result, tumor growth is initially repressed, and then reversed. Another type of chemotherapeutic is referred to as an alkylating agent. These compounds function by inserting foreign compositions or molecules into the DNA of dividing cancer cells. As a result of these foreign moieties, the normal functions of cancer cells are disrupted and proliferation is prevented. Another type of chemotherapeutic is an antineoplastic agent. This type of agent prevents, kills, or blocks the growth and spread of cancer cells. Still other types of anticancer agents include nonsteroidal aromastase inhibitors, bifunctional alkylating agents, etc.
Paclitaxel represents one of the major classes of antimicrotubule agents that promotes tubulin polymerization and, presumably, mitotic arrest during cell division. Taxol (paclitaxel) has been shown to have excellent antitumor activity in vivo and has been employed in the treatment of a variety of cancers, including breast, ovarian and lung cancer. Unfortunately, many tumors develop resistance to paclitaxel.
Epothilones mimic the biological effects of taxol, (Bollag et al., Cancer Research 55: 2325–2333 (1995), and in competition studies act as competitive inhibitors of taxol binding to microtubules. However, epothilones enjoy a significant advantage over taxol in that epothilones exhibit a much lower drop in potency compared to taxol against a multiple drug-resistant cell line (Bollag et al. (1995)). Furthermore, epothilones are considerably less efficiently exported from the cells by P-glycoprotein than is taxol (Gerth et al. (1996)).
It is an object of the invention to provide efficacious combination chemotherapeutic treatment regimens wherein epothilone analogs are combined with other anti-neoplastic agents for the treatment of proliferative diseases.